Reperfusion Injury Protection Strategies During Basic Life Support

描述(由申请人提供)：院外心脏骤停在美国仍然是一个严重的健康问题。尽管尽了最大努力进行心肺复苏(CPR)，但每年仍有超过35万名患者死亡或有严重的神经功能障碍。尽管心肺复苏成功与否和预后与心肺复苏持续时间成反比，但我们有理由相信，在心肺复苏初期，由于血流重新注入而引起的突然的分子和代谢变化比脑缺血本身造成的损伤更具危害性。因此，对于这项竞争性的变革性研究奖，我们提出了几种新的且易于应用的策略来减轻再灌注损伤(RI)的发展：缺血后处理(IPC)，即通过间歇性停止胸部按压来控制血流暂停，以及在CPR的前3分钟通过肺给予七氟醚或氦等吸入剂(IAPC)的药物后处理。尽管目前的心肺复苏标准看似矛盾和具有挑战性，但我们认为，对这些预防RI的保护技术的机制、安全性和有效性的拟议研究可能会从根本上改变传统的临床范式。为了实现我们的总体目标，即每年提高数千名患者的神经学上的完整存活率，我们提议的项目的目标是测试不同的后处理策略(IPC，IAPC)及其组合，描述它们随着时间的推移对器官保护的发展，并阐明它们的细胞内信号机制。根据初步结果，我们推测，与标准CPR相比，IPC和/IAPC复苏时增加的一氧化氮产生和延迟的线粒体通透性转换孔道开放是动物复苏显著改善的原因。在一个已建立的猪模型上，我们将在三个交错的特定目标中，通过将早期和延迟的IPC和IAPC整合到CPR中来评估心脏、大脑、肾脏和肝脏的保护。结果将与目前治疗低温的黄金标准进行比较。最先进的血液动力学测量、器官特异性生物标志物、组织组织学、线粒体研究和神经学测试将对每个系统中观察到的保护提供全面的定量和定性评估。令人信服的初步证据，加上来自三个不同学术机构的研究人员的丰富专业知识，使这是一种最有希望、最具创新性和独一无二的方法，其结果提供了极大的潜力，可以影响未来复苏领域的研究和临床护理。

DESCRIPTION (provided by applicant): Out-of-hospital cardiac arrest (OHCA) remains a severe health problem in the United States. More than 350,000 patients die or have severe neurological deficits each year despite best efforts in cardiopulmonary resuscitation (CPR). Although successful resuscitation and outcome are inversely proportional to the duration of OHCA, we have reason to believe that the abrupt molecular and metabolic changes resulting from reintroduction of blood flow during initial CPR are more harmful than the injury caused by the ischemia itself. Accordingly, for this competitive Transformative Research Award we propose several novel and readily applicable strategies to mitigate the development of reperfusion injury (RI): ischemic postconditioning (IPC), i.e., controlled pauses of blood flow by intermittently stopping chest compressions, and pharmacological postconditioning with inhaled agents (IAPC) such as sevoflurane or helium administered through the lungs during the first 3 min of CPR. Though seemingly contradictory and challenging current standard-of-care CPR, we submit, however, that the proposed study of mechanisms, safety, and efficacy of these protective techniques against RI could fundamentally change traditional clinical paradigms. In pursuit of our overall goal to improve neurologically intact survival for OHCA for thousands of patients each year, the objectives of our proposed project are to test different postconditioning strategies (IPC, IAPC) and their combination, to characterize their organ-protective development over time, and to elucidate their intracellular signaling mechanisms. Based on preliminary results, we hypothesize that increased nitric oxide production and delayed mitochondrial permeability transition pore opening are responsible for the dramatic improvement in animals when resuscitated with IPC and/IAPC compared to standard CPR. In three staggered specific aims we will assess cardiac, cerebral, renal and hepatic protection by integrating early and delayed IPC and IAPC into CPR following prolonged ventricular fibrillation in an established pig model. Results will be compared with the current gold-standard of therapeutic hypothermia. State- of-the-art hemodynamic measurements, organ-specific biomarkers, tissue histology, mitochondrial studies and neurological testing will provide a comprehensive quantitative and qualitative assessment of the observed protection in each system. Convincing preliminary evidence together with the wealth of expertise of researchers from three different academic institutions make this a most promising, innovative and unique approach whose results offer exceptional potential to influence research and clinical care in the field of resuscitation for yeas to come.